Emerging Gene Therapies for Alzheimer’s and Parkinson’s Diseases: An Overview of Clinical Trials and Promising Candidates

Gene therapy as a disease-modifying therapeutic approach for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is a promising avenue. Promising results in the preclinical studies involving rodents and nonhuman primates utilizing gene therapy have led to multiple clinical trials evaluating various genes of interest for AD and PD. In AD, clinical trials are assessing gene therapy involving brain-derived neurotrophic factor (BDNF) and other targets such as apolipoprotein E2 (APOE2) and human telomerase reverse transcriptase (hTERT). In PD, clinical trials are evaluating gene therapy delivering neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). Additionally, gene therapy delivering enzymes aromatic L-amino acid decarboxylase (AADC) and glutamic acid decarboxylase (GAD) are also being evaluated for PD. All these trials primarily utilized adeno-associated virus (AAV) to deliver the above transgene of interest. This review summarizes the current clinical trials involving gene therapy for AD and PD. It also discusses the challenges and opportunities associated with the gene therapy approach in AD and PD and ongoing developments related to increasing the safety and efficacy of the gene therapy for long-term outcomes, which include evaluation of various serotypes and administration routes. This comprehensive review emphasizes translating preclinical findings into clinical trials, further directions, and the potential for this promising therapeutic approach to alleviate neurodegenerative disease.